ZA200303771B - Improved treatment. - Google Patents
Improved treatment. Download PDFInfo
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- ZA200303771B ZA200303771B ZA200303771A ZA200303771A ZA200303771B ZA 200303771 B ZA200303771 B ZA 200303771B ZA 200303771 A ZA200303771 A ZA 200303771A ZA 200303771 A ZA200303771 A ZA 200303771A ZA 200303771 B ZA200303771 B ZA 200303771B
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- South Africa
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- combination
- iop
- prostaglandin
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- 238000011282 treatment Methods 0.000 title description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 44
- 150000003180 prostaglandins Chemical class 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 30
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 claims description 28
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 26
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 26
- 229960004605 timolol Drugs 0.000 claims description 26
- 229960001160 latanoprost Drugs 0.000 claims description 25
- 208000010412 Glaucoma Diseases 0.000 claims description 21
- 210000001742 aqueous humor Anatomy 0.000 claims description 20
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- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 6
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- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 claims 2
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- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 1
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- 208000021822 hypotensive Diseases 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Glass Compositions (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
Description
Improved treatment
Glaucoma is generally described as a group of ocular conditions, which involve ' 5 progressive optic nerve damages, and the loss of visual functions. The pathogenesis of the optical nerve damage remains unclear, but it is widely accepted that a chronic elevation of the intraocular pressure (IOP) is an important factor in glaucoma damage development. The generation of ocular hypertension is associated with an impaired circulation of aqueous humor in the eye which in many cases is the result of an imbalance between the formation of aqueous humor and impaired outflow mechanisms through the trabecular meshwork and Schlemm’s canal in the anterior chamber. Conventionally, glaucoma is diagnosed if two of the three criteria among elevated IOP, optical nerve head damage and visual field loss are found in the same of eye a patient.
Nevertheless, it is clinically established to prescribe a therapy to individuals, which are exposed to chronic IOP elevation in order to minimize the risk that they acquire irreparable visual damages associated with diagnosed glaucoma. The most widespread IOP-reducer has been the beta-adrenergic agent timolol, which is exerting its effect by reducing the production of aqueous * humor and thereby contribute to alleviate the impaired turn-over of aqueous humor of the eve.
Recent clinical developments in ophthalmology in terms of glaucoma therapy have established the prostaglandin F-, derivative latanoprost (marketed as Xalatan® by Pharmacia Corp.) as a potent and useful Fa, intraocular pressure reducer with few side effects. Since the IOP reducing : effect of prostaglandin F,, derivatives including latanoprost has been attributed to their capacity of increasing the uveoscleral outflow of aqueous humor, it has been suggested to combine it with other known IOP-reducing agents exerting their effect through a different mechanism in order to obtain an additive effect. For this reason, combination therapy with beta-adrenergic agonists was '5 early suggested, see European Patent No. 0286903 and US Patents Nos. 5,405,846 and 5,166,175.
For example, P Hoyng et al in Survey Ophthalmol. 1997, 41(Suppl. 2), S93 disclose studies made on latanoprost and timolol that demonstrates an additive IOP-reducing effect in patients suffering from an elevated [OP and having an insufficient response to timolol alone. There are several studies directed to investigate the IOP reducing effects from adjunctive therapy of the beta- 0 adrenergic agonist timolol and latanoprost, which suggest that the combination results in a more pronounced hypotensive effect than can be achieved from any of the two drugs alone, see N
Pfieffer in IOVS 2000, 41(4), S754; B Sjoquist et al in 10VS 2000, 41(4), S572; LI Larsson in
IOVS 2000, 41(4), S280; P Hyong et al in Drugs 2000, 59(3), 411-434; WC Stewart et al in J
Ocul Pharmacol Ther, 2000, 16(3), 251-259; K Iishi et al in Jpn J Ophthalmol, 2000, 44(3), 227-
234; PT Hung et al in Am J Ophthalmol, 1999, 128(6), 692-696; PG Watson in Drugs Today, 1999, 35(6), 449-459; C Linden et al in Drugs Aging, 1999, 14(5), 3 87-398; L Martin in Acta . Ophthalmol Scand, 1999, 77(3), 336-339; TW Heijkal et al in Seminars in Ophthalmology, 1998, 14(3), 114-123; M Diestelhorst et al in Graefe’s Arch Clin Exp Ophthalmol, 1998, 236(8), 577- * 5 581 and A Alm et al in British J Ophthalmol, 1995, 79(1), 12-6. Furthermore, there are several non-prostaglandin containing fixed combinations available for the treatment of glaucoma based on a beta-adrenergic antagonist and a complementary agent with ocular hypotensive effect.
Normoglaucon® contains 0.1% metipranolol and 2% pilocarpine. TP-2® or Timpilo-2® contains 0.5% timolol and 2% pilocarpine. Cosopt® contains 0.5% timolol and 2% dorzolamide.
Given that the course of development of glaucoma is unpredictable with a pathogenesis largely varying among individuals, frequently with unnoticeable symptoms and signs, certain patients may have reached an advanced stage of the disease with visual field loss as a result of optical nerve damage, even before they are examined by medical expertise. For this type of patients, it is necessary to institute a radical IOP-reducing treatment. However, conventional IOP- reducers frequently are insufficient to reach suitable results and surgical intervention may be necessary to restore the turn-over of aqueous humor by improving its outflow. Although treatments with combination of IOP-reducing agents which affect the IOP-reduction according to different mechanisms have been suggested to generate additive effects beyond each individual agent, there are so far no indications that any combination therapy would have an especial efficacy for patients suffering from advanced glaucoma. It would therefor be desirable to provide for a therapeutic treatment that was especially efficient in reaching such patients who are suffering from these advanced stages of glaucoma who are at serious risk to acquire further loss of vision to an extent that would compromise their quality of life.
It is an object of the present invention to provide for a therapy according to which particular high-risk glaucoma patients can be treated with greater efficacy.
It is another object of the present invention to provide for a therapy for patients with a particular risk factor of acquiring advanced glaucoma can be treated with higher efficacy. ' It is a particular object of the present invention to employ a combination of IOP-reducing agents for simultaneous administration and thereby obtain an improved IOP-reducing efficacy in severe glaucoma patients and individuals having an especial need of a high IOP reduction.
The present invention resides in the finding that a therapy of two or more agents with capacity of reducing the intraocular pressure has an improved efficacy to treat advanced : glaucoma in such patients who suffer from detectable vision related impairments, when said agents are administered simultaneously. In the inventive context, simultaneous administration ’ 5 means that the agents are delivered to the eye substantially at the same time, for example subsequently immediately after each other, or that they are co-administered as a mixture.
Dependent on the characteristics of the agents they can be pre-mixed in a ready-made solution, or for stability reasons separately stored and mixed, just prior to the administration. There are many devices available to skilled practitioners to prepare a solution in-situ and these are not described in any detail herein as they not are a part of the present invention. It is preferred that the combination is a mixture of agents that can be applied to the surface of the eye in the form of a topical ophthalmic preparation delivered in drop form or delivered in the form of a directed stream from a pressurized ophthalmic dispenser.
It has been surprisingly found that the IOP reducing capacity arrived from a combination treatment in such patients significantly exceeds IOP reduction in patients exposed to an IOP increase, who thereby are at risk of obtaining visual damages, but not yet having acquired such advanced stages of the ailment. The inventive method will be particularly useful for the mentioned patients and also for individuals in particular need of a high reduction of IOP due to the exposure of certain risk factors which can be considered to aggravate or accelerate the visual complications arriving from exposure to ocular hypertension. Such individuals include those who belong to family with a history of glaucoma cases and individuals suffering from conditions which may trigger ischemic complications in the region of the optical nerve head. The skilled practitioner will be able to sort out individuals who would be extra susceptible to acquire damages from elevated IOP and thereby will be elected to undergo a combination therapy.
In the context of the present invention advanced glaucoma or severe glaucoma shall be defined as a condition where an individual has acquired an optical nerve damage, i.e. abnormalities of the optical nerve head and defects of the visual field. Both these damages can be detected by standard methods available to ophthalmologists. The presence of an optical nerve ‘damage can be objectively measured for example by laser scanning tomography to measure the nerve fiber thickness, see LM Zangwill et al. Optometry and Vision Science, 1999, 76(8), pp. ’ 526-36 or the similar methods to objectively estimate the loss of tissue. Visual field loss can be measured by conventional methods employed by ophthalmologists.
In further context of the present invention, a combination of IOP reducers is defined as at least two different agents with IOP reducing capacity acting according to different mechanisms in their to provide the reduction when they are concomitantly administered. For example, such differences in mechanistic onset of the IOP-reduction could include stimulation (affinity to) of . different receptors in the eye, however, not necessary located at different sites of the eye.
Accordingly, different prostaglandin derivatives with different prostaglandin receptor profiles can : 5 be used, such as a prostaglandin derivative predominantly exerting its IOP-receptor effect through the FP receptor could be combined with one or several prostaglandins exerting is IOP-reducing effect less selectively by a pronounced affinity to other of eight major prostaglandin receptors.
Preferably, a combination of IOP-reducers having different physiological actions is used in the present invention. A suitable combination would be one agent increasing the outflow of aqueous humor and one agent reducing its formation of aqueous humor. A typical combination of an JOP reducing effective amount of a prostaglandin derivative together with at least one IOP reducing agent exerting its activity through other receptors than prostaglandin receptors.
Particularly useful are prostaglandins or prostaglandin derivatives capable of reducing IOP by increasing the uveoscleral outflow in combination with one or several IOP-reducing agents having another physiological action. Such prostaglandins are found among prostaglandin Fy, (PGF,,) analogues and derivatives such as those discussed in US Patent 4,599,353. Preferably, the prostaglandin F,, derivatives have the carboxyl group in the alpha-chain substituted with a lower alkyl ester, such as isopropyl ester, to improve corneal penetration. Alternatively, said carboxyl group can be substituted with alcohol or ether or the similar for rendering the compound more lipophilic. Especially useful such PGF, derivatives have ring-formed substituent in the terminal of the omega-chain of the prostaglandin F», structure, such as 13,14-dihydro-17-phenyl-18,19,20- trinor-prostglandin F,,-isopropyl ester (latanoprost), 16-(meta-trifluromethyl)-phenoxy- 17,18,19,20-tetranor-prostglandin F,-isopropyl ester (travaprost) and similar compounds referred "to in WO 90/02553. Ring-formed substituent is defined as an aryl group, an arylalkyl group, a 1S heterocyclic aromatic group or a cycloalkyl group which optionally is substituted. Also useful, however less potent than the aforementioned compounds, is the PGF,,-metabolite analogue isopropyl unoprostone. Numerous other prostaglandin derivatives are described in the literature as ocular hypotensive agents or anti-glaucoma agents under denominations deviating from prostaglandin nomenclature, such as hypotensive lipids and the similar. Obviously, such 0 compounds also will be a part of the present invention.
An IOP-reducing prostaglandin according what is stated above preferably is combined with at least one IOP reducing agent selected among cholinergic agonists (such as pilocarpine), beta-adrenegic antagonists (such as timolol), carbonic anhydrase inhibitors (such as acetazoloamide or dorzolamide) or beta-adrenergic agonists (such as dipivefrine). More suitably,
i WO 02/38158 PCT/SE01/02499 said prostaglandin is combined with one or several IOP-reducing agent capable of affecting the formation of the aqueous humor, such as a carbonic anhydrase inhibitor or a beta-adrenergic . antagonist (beta-blocker). Especially preferred is a combination of a prostaglandin and a beta- adrenergic antagonist in the form of an ophthalmically acceptable composition for topical - 5 administration to the eye. Suitably the prostaglandin is a prostaglandin F,, derivative with capacity of increasing the uveoscleral outflow, such as latanoprost, travaprost or isopropyl unoprostone. The beta-adrenergic antagonist is selected among conventional such agents including, but not limited to, acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, carteolol, celiprolol, esmolol, labetalol, levobunolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol. Especially preferable beta-adrenergic antagonist are timolol maleate, betaxolol hydrochloride, levobunolol hydrochloride and metipranolol.
The inventive therapy is conducted with regular doses of the combination, such as in the form of eye drops each having a volume of about 30 pl. Typically such a dose comprises about 0.1 to 1000 pg, preferably 0.1 to 50 pg of prostaglandin derivative and beta-adrenergic agents in the range of about 0.01 pg to 1000 ng, preferably from about 5 pg to 500 pg.
An especially preferred combination is a topical ophthalmic composition of the PGF, derivative latanoprost and the beta-blocker timolol. The composition further comprises conventional additives rendering it suitable for topical ophthalmic administration, such as preservatives and solubilizers. Typically, such a composition comprises from about 0.001 to 0.01%(w/v) of latanoprost and from about 0.1 to 2% (w/v) of timolol.
A greatly preferred composition to included in the combination comprises 0.5 % (5 mg/ml) timolol and 0.005 % (50 ug/ml) latanoprost together with one or several buffering agents, a preservative or solubilizer, a tonicity agent and one or several pH adjustment agents. *5 A specific example of composition useful in the present invention contains:
a ES EN 10% solution Sodium q.s. to pH 6.0 if required pH adjustment
Il ll a
The composition will be packaged as a sterile eye drops product in 5 mi bottles suitable for administering 30 pl drop dosages to the surface of the eye.
In the following experimental section, it has been demonstrated that a combination therapy as exemplified with the combination of latanoprost and timolol has an unexpected efficacy for patients suffering from severe glaucoma.
Exemplifying part of the description
A sub-population of 76 individuals in a population of total 854 patients enrolled into two different studies of German patients (004) and US patients (005) were identified at baseline as having some degree of abnormality to the optic nerve head together with a glaucomatous visual field defect and were treated with a fixed combination (FC) of latanoprost and timolol. Both studies were based on a randomized double-masked parallel group design. In both studies, a fixed combination (FC) of latanoprost and timolol was administered to a group of patients with optic nerve head damage and visual field loss (i.e. glaucomatous field defects) and to groups of patients without any such detected damages, but with an elevation of IOP. Patient demography and baseline characteristics in patients with and without optic nerve head damages and glaucomatous 0 field defects are shown in Table 2.1.
The patients is the studies received one drop in the morning of a fixed combination of latanoprost (50 pg/ml) and timolol (Smg/ml) during the study duration of 26 weeks. The exact composition of fixed combination is disclosed in Table 1. At baseline, IOP assessments were made at 08:00, 10:00, and 16:00. Measurements at the same time-points were subsequently made ‘ '5 at scheduled clinic visits at Week 2, Week 13, and Week 26. Additionally, an 08:00 measurement was also obtained at Week 6. The patients have an approximately 5 mm Hg decrease in IOP from a timolol run-in period.
Claims (69)
1. A combination of IOP reducing agents for use in a method of treating a patient suffering from severe glaucoma, exhibiting optical nerve head damage and visual field defects, comprising simultaneously administering the combination of IOP-reducing agents to the patient’s eye, wherein at least one IOP-reducing agent comprises a prostaglandin or a prostaglandin derivative and at least one IOP-reducing agent comprises a beta-adrenergic antagonist or carbonic anhydrase inhibitor.
2. A combination according to claim 1, wherein said combination is administered to the surface of the eye.
3. A combination according to claim 2, wherein said combination is a topical ophthalmic composition comprising a mixture of IOP-reducing agents.
4, A combination according to claim 1, wherein improved efficacy in IOP reduction is obtained in the patient when compared to patients suffering from an elevated IOP, but being free from abnormalities in the optical nerve head and visual field loss.
5. A combination according to claim 1, wherein said combination comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
6. A combination according to claim 1, wherein said prostaglandin comprises an IOP reducing amount of a prostaglandin F,, derivative.
7. A combination according to claim 6, wherein said prostaglandin F,, derivative has an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
8. A combination according to claim 7, wherein said prostaglandin F, , is latanoprost or travaprost. Amended Sheet — 2004-07-27
9. A combination according to claim 6, wherein said prostaglandin F,, derivative is isopropyl unoprostone.
10. A combination according to claim 1, wherein said combination comprises an effective amount of an IOP-reducing agent capable of reducing the formation of aqueous humor.
11. A combination according to claim 10, wherein said combination further comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
12. A combination according to claim 1, wherein said combination comprises a prostaglandin F,y derivative and a beta-adrenergic antagonist.
13. A combination according to claim 12, wherein said combination comprises a prostaglandin F, derivative having an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
14. A combination according to claim 13, wherein said combination comprises latanoprost and timolol.
15. A combination according to claim 14, wherein said combination is a mixture of latanoprost and timolol in a topical ophthalmic composition.
16. A combination of IOP reducing agents for use in a method of treating an individual in need of a high IOP reduction comprising simultaneously administering the combination of IOP- reducing agents to the eye, wherein at least one IOP-reducing agent comprises a prostaglandin or a prostaglandin derivative and at least one IOP-reducing agent comprises a beta-adrenergic antagonist or carbonic anhydrase inhibitor.
17. A combination according to claim 16, wherein said individual has a hereditary disposition for glaucoma. Amended Sheet — 2004-07-27
18. A combination according to claim 16, wherein said individual suffers from complications which may trigger ischemic conditions in the region of the optical nerve head.
19. A combination according to claim 16, wherein said individual suffers ocular hypertension without detected damages of the optical nerve head or a loss of the visual field.
20. A combination according to claim 16, wherein said combination is administered to the surface of the eye.
21. A combination according to claim 18, wherein said combination is a topical ophthalmic composition comprising a mixture of IOP-reducing agents.
22. A combination according to claim 16, wherein said combination comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
23. A combination according to claim 16, wherein said prostaglandin comprises an IOP reducing amount of a prostaglandin F,, derivative.
24, A combination according to claim 23, wherein said prostaglandin F,, derivative has an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
25. A combination according to claim 24, wherein said prostaglandin F,, is latanoprost or travaprost.
26. A combination according to claim 25, wherein said prostaglandin F,, derivative is isopropyl unoprostone.
27. A combination according to claim 16, wherein said combination comprises an effective amount of an IOP-reducing agent capable of reducing the formation of aqueous humor. Amended Sheet —- 2004-07-27
28. A combination according to claim 27, wherein said combination further comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
29. A combination according to claim 16, wherein said combination comprises a prostaglandin F,, derivative and a beta-adrenergic antagonist.
30. A combination according to claim 29, wherein said combination comprises a prostaglandin F,, derivative having an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
31. A combination according to claim 30, wherein said combination comprises latanoprost and timolol.
32. A combination according to claim 31, wherein said combination is a mixture of latanoprost and timolol in a topical ophthalmic composition.
33. The use of a combination of IOP-reducing agents for the preparation of a composition for use in simultaneously administering the combination of IOP-reducing agents to the patient’s eye in a method of treating a patient suffering from severe glaucoma, exhibiting optical nerve head damage and visual field defects, wherein at least one IOP-reducing agent comprises a prostaglandin or a prostaglandin derivative and at least one IOP-reducing agent comprises a beta- adrenergic antagonist or carbonic anhydrase inhibitor.
34. The use according to claim 33 for the preparation of a composition for administration to the surface of the eye.
35. The use according to claim 34, wherein said composition comprises a mixture of IOP- reducing agents. Amended Sheet — 2004-07-27
36. The use according to any of claims 33 to 35, wherein said composition improves the efficacy in IOP reduction in the patient when compared to patients suffering from an elevated . IOP, but being free from abnormalities in the optical nerve head and visual field loss.
37. The use according to any of claims 33 to 36, wherein said combination comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
38. The use according to claim 33, wherein said prostaglandin comprises an [OP reducing amount of a prostaglandin F,, derivative.
39. The use according to claim 38, wherein said prostaglandin F,, derivative has an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
40. The use according to claim 39, wherein said prostaglandin F; , is latanoprost or travaprost.
41. The use according to claim 40, wherein said prostaglandin F;, derivative is isopropyl Unoprostone.
42. The use according to claim 33, wherein said combination comprises an effective amount of an IOP-reducing agent capable of reducing the formation of aqueous humor.
43. The use according to claim 42, wherein said combination further comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
44, The use according to claim 43, wherein said combination comprises a prostaglandin F,, derivative and a beta-adrenergic antagonist.
45. The use according to claim 44, wherein said combination comprises a prostaglandin Fy, derivative having an omega chain carrying a ring substituent in a terminal position, selected from Amended Sheet — 2004-07-27 the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
46. The use according to claim 45, wherein said combination comprises latanoprost and timolol.
47. The use according to claim 46, wherein said combination is a mixture of latanoprost and timolol in a topical ophthalmic composition.
43. The use of a combination of IOP reducing agents in the preparation of composition for use in simultaneously administering the combination of IOP-reducing agents to the eye in a method of treating an individual in need of a high IOP reduction, wherein at least one IOP- reducing agent comprises a prostaglandin or a prostaglandin derivative and at least one IOP- reducing agent comprises a beta-adrenergic antagonist or carbonic anhydrase inhibitor.
49. The use according to claim 48, wherein said individual has a hereditary disposition for glaucoma.
50. The use according to claim 48, wherein said individual suffers from complications which may trigger ischemic conditions in the region of the optical nerve head.
51. The use according to claim 48, wherein said individual suffers from ocular hypertension without detected damages of the optical nerve head or a loss of the visual field.
52. The use according to claim 48, wherein said combination is administered to the surface of the eye.
53. The use according to claim 52, wherein said combination is a topical ophthalmic composition comprising a mixture of IOP-reducing agents.
54. The use according to claim 48, wherein said combination comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor. Amended Sheet — 2004-07-27
55. A use according to claim 48, wherein said prostaglandin comprises an IOP reducing amount of a prostaglandin F,, derivative.
56. A use according to claim 55, wherein said prostaglandin F,, derivative has an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
57. A use according to claim 56, wherein said prostaglandin F,, is latanoprost or travaprost.
58. A use according to claim 55, wherein said prostaglandin F,, derivative is isopropyl unoprostone.
59. A use according to claim 48, wherein said combination comprises an effective amount of an IOP-reducing agent capable of reducing the formation of aqueous humor.
60. A use according to claim 59, wherein said combination further comprises an effective amount of an IOP-reducing agent capable of increasing the uveoscleral outflow of aqueous humor.
61. A use according to claim 48, wherein said combination comprises a prostaglandin F,, derivative and a beta-adrenergic antagonist.
62. A use according to claim 61, wherein said combination comprises a prostaglandin Fy, derivative having an omega chain carrying a ring substituent in a terminal position, selected from the group consisting of optionally substituted phenyl, cycloalkyl and aromatic heterocyclic groups.
63. A use according to claim 62, wherein said combination comprises latanoprost and timolol.
64. A use according to claim 63, wherein said combination is a mixture of latanoprost and timolol in a topical ophthalmic composition. Amended Sheet — 2004-07-27
65. A method according to claim 16, wherein the individual exhibits optical nerve head damage and visual field defects.
66. A combination according to claim 1, wherein said combination comprises a prostaglandin
F, . derivative and a carbonic anhydrase inhibitor.
67. A combination according to claim 16, wherein said combination comprises a prostaglandin F,, derivative and a carbonic anhydrase inhibitor.
68. A combination according to claim 1, wherein the beta-adrenergic antagonist comprises acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, carteolol, celiprolol, esmolol, labetalol, levobunolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol or timolol.
69. A combination according to claim 16, wherein the beta-adrenergic antagonist comprises acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, carteolol, celiprolol, esmolol, labetalol, levobunolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol or timolol. Amended Sheet — 2004-07-27
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| AU2003222049B2 (en) * | 2002-03-21 | 2007-05-31 | Cayman Chemical Company, Incorporated | Prostaglandin F2 alpha analogs in combination with antimicrobials for treating glaucoma |
| EP2314299A1 (en) | 2002-08-29 | 2011-04-27 | Santen Pharmaceutical Co., Ltd | Therapeutic agent for glaucoma comprising rho kinase inhibitor and prostaglandin |
| US7074827B2 (en) * | 2002-10-24 | 2006-07-11 | Sucampo Ag (Usa) Inc. | Method for treating ocular hypertension and glaucoma |
| KR101223886B1 (en) * | 2002-11-18 | 2013-01-17 | 산텐 세이야꾸 가부시키가이샤 | REMEDY FOR GLAUCOMA COMPRISING Rho KINASE INHIBITOR AND β-BLOCKER |
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| EP3002277B1 (en) | 2004-01-05 | 2019-11-06 | Nicox S.A. | Prostaglandin derivatives |
| EP1759702B1 (en) | 2004-05-26 | 2009-01-07 | Arturo Jimenez Bayardo | Method of preparing a latanoprost ophthalmic solution and solution thus produced |
| GB0501192D0 (en) * | 2005-01-20 | 2005-03-02 | Resolution Chemicals Ltd | Stable prostaglandin-containing compositions |
| KR101326425B1 (en) | 2005-06-21 | 2013-11-11 | 코와 가부시키가이샤 | Preventive or remedy for glaucoma |
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| WO2010119305A1 (en) * | 2009-04-14 | 2010-10-21 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Using of quaternary ammonium compounds in dissolving of latanoprost |
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| JP6023082B2 (en) * | 2011-01-24 | 2016-11-09 | インセプタム リサーチ アンド セラピューティクス，インク． | Compositions containing prostaglandins for treating neuropsychiatric diseases |
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| NO20032122D0 (en) | 2003-05-12 |
| NZ525817A (en) | 2005-03-24 |
| NO20032122L (en) | 2003-07-01 |
| BR0115208A (en) | 2003-10-07 |
| JP2004513148A (en) | 2004-04-30 |
| EP1333837A1 (en) | 2003-08-13 |
| HUP0400548A2 (en) | 2004-06-28 |
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